rs2915954

Variant names:

• chr19-38506000-A-G
• rs2915954
• NM_000540.3:c.8541+54A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-38506000-A-G
• chr19-38506000-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000540.3(RYR1):​c.8541+54A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,479,342 control chromosomes in the GnomAD database, including 60,377 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene RYR1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.32 (8434 hom., cov: 29)
  • Exomes 𝑓: 0.25 (51943 hom.)
• Consequence: RYR1 NM_000540.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -2.60
• Publications: 5 publications found

Genes affected

RYR1 (HGNC:10483): (ryanodine receptor 1) This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

RYR1 Gene-Disease associations (from GenCC):

• malignant hyperthermia, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• RYR1-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia
• congenital multicore myopathy with external ophthalmoplegia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P
• central core myopathy

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• King-Denborough syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant hyperthermia of anesthesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive centronuclear myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• benign Samaritan congenital myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital myopathy with myasthenic-like onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for RYR1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-38506000-A-G is Benign according to our data. Variant chr19-38506000-A-G is described in ClinVar as Benign. ClinVar VariationId is 133229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000540.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	NM_000540.3	MANE Select	c.8541+54A>G		intron	N/A	NP_000531.2	P21817-1
	RYR1	NM_001042723.2		c.8541+54A>G		intron	N/A	NP_001036188.1	P21817-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RYR1	ENST00000359596.8	TSL:5 MANE Select	c.8541+54A>G		intron	N/A	ENSP00000352608.2	P21817-1
	RYR1	ENST00000355481.8	TSL:1	c.8541+54A>G		intron	N/A	ENSP00000347667.3	P21817-2
	RYR1	ENST00000594335.6	TSL:1	n.8541+54A>G		intron	N/A	ENSP00000470927.2	M0R014

Frequencies

GnomAD3 genomes AF: 0.324 AC: 48749 AN: 150678 Hom.: 8397 Cov.: 29

Gnomad AFR AF: 0.428

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.457

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.318

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.334

GnomAD4 exome AF: 0.249 AC: 331117 AN: 1328542 Hom.: 51943 AF XY: 0.256 AC XY: 170086 AN XY: 664558

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.414 AC: 12428 AN: 30018

American (AMR) AF: 0.385 AC: 16689 AN: 43358

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 6115 AN: 25224

East Asian (EAS) AF: 0.332 AC: 12840 AN: 38632

South Asian (SAS) AF: 0.438 AC: 35711 AN: 81500

European-Finnish (FIN) AF: 0.285 AC: 13763 AN: 48268

Middle Eastern (MID) AF: 0.307 AC: 1282 AN: 4182

European-Non Finnish (NFE) AF: 0.217 AC: 217086 AN: 1001598

Other (OTH) AF: 0.273 AC: 15203 AN: 55762

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.324 AC: 48848 AN: 150800 Hom.: 8434 Cov.: 29 AF XY: 0.331 AC XY: 24360 AN XY: 73604

African (AFR) AF: 0.429 AC: 17587 AN: 40980

American (AMR) AF: 0.354 AC: 5369 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 882 AN: 3452

East Asian (EAS) AF: 0.357 AC: 1816 AN: 5090

South Asian (SAS) AF: 0.457 AC: 2173 AN: 4752

European-Finnish (FIN) AF: 0.286 AC: 2986 AN: 10436

Middle Eastern (MID) AF: 0.315 AC: 92 AN: 292

European-Non Finnish (NFE) AF: 0.251 AC: 16996 AN: 67620

Other (OTH) AF: 0.339 AC: 710 AN: 2096

Alfa AF: 0.287 Hom.: 765

Bravo AF: 0.332

Asia WGS AF: 0.483 AC: 1671 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.17
DANN	Benign	0.85
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2915954;

hg19: chr19-38996640;